Proteasome inhibitors and modulators of angiogenesis in multiple myeloma

Survival of patients affected by Multiple Myeloma (MM), a B-cell tumor of malignant plasma cells, has dramatically improved, owing to the recent introduction of the proteasome inhibitor (PI) Bortezomib and of the immunomodulatory drugs (IMiDs). This major advance originates from accumulating knowledge on MM biology, leading to the development of drugs targeting not only MM cells, but also their microenvironment. Indeed, the disease develops as a result of genetic abnormalities and of reciprocal interactions between MM cells and the permissive BM microenvironment, which delivers growth- and pro-survival signals and confers resistance to drugs. As for solid tumors, bone marrow (BM) angiogenesis is emerging as a critical component of MM development and progression, and hence as an attractive therapeutic target for the disease. The patho-physiology of MM associated angiogenesis is complex and involves a plethora of soluble factors, cellular players and mechanisms. Moreover, the hypoxic microenvironment inside the BM might significantly contribute to the induction and maintenance of a pro-angiogenic profile, given the well-known role of hypoxia in promoting angiogenesis in all its forms. Here we present an overview of the literature focusing on the mechanisms implicated in the "angiogenic switch", which corresponds to the transition from the avascular to the vascular phase of the disease. We also review evidence on the anti-angiogenic effects of PI and IMiDs, which substantially contribute to their anti-MM activity. Finally, we summarize possible caveats and perspectives about antiangiogenic strategies that could be addressed to improve the efficacy of treatments for MM patients.